Pharmaceutical Technology - October 2021


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32 Pharmaceutical Technology APIs, EXCIPIENTS, AND MANUFACTURING eBOOK 2021 P h a r mTe c h . c o m Manufacturing Table I, is used as a formulation development tool to help assess the best formulation for an API. The DCS categorizes APIs according to their dose solubility ratio and permeability. Those APIs that are amenable to simple tableting or powder-in-capsule delivery are likely to fall into Class I, as molecules that are both soluble at their administered dose and fully permeable, whereas those that are neither soluble at a given dose nor permeable, fall into Class IV. Many drugs now in development fall into Class II, having low solubility at the given dose but high permeability. Drugs that have poor permeability properties but readily dissolve represent DCS Class III compounds. The DCS gives greater insight into the solubility behavior of molecules in Class II, by splitting it into two sub-classifications. This split is made based on the concept of a solubility-limited absorbable dose (SLAD), which represents the dose above which absorption of a compound is limited by its solubility. At doses below the SLAD, designated DCS IIa compounds, a drug's absorption is limited by its dissolution rate, whereas at doses above the SLAD, the absorption is limited by the drug's intrinsic solubility. These are designated DCS IIb compounds. Micronization is effective at improving the dissolu- tion rate for DCS Class IIa compounds and making them easier to dissolve. It is not typically the primary tool to address the challenges of DCS IIb molecules, but for those that are close to the border between DCS IIa and IIb, co-micronization can be an effec- tive method to improve solubility. Co-micronization consists of two steps: blending the API with an appropriate surfactant and subjecting the mixture to the standard micronization process. The surfactant enables more of the drug to dissolve and is more commonly used to overcome develop- ment challenges with drugs that are both highly po- tent but poorly soluble. Along with improving solu- bility, co-micronization can improve flowability of micronized powders, reduce re-agglomeration, and improve the wettability of micronized particles. Jet milling process Of the micronization options available to devel- opers, jet milling is one of the most common, as it allows material with an average particle size of 1–10 microns to be produced. A jet mill has no moving parts, does not heat up, and is relatively simple to operate. Jet mills use high-pressure nitrogen gas to force the API into the mill, where the API particles collide with each other and the sides of the mill, reducing particle size. The f lexibility and scalability of the process allows quantities from just a few grams of API, right through to metric ton quantities, to be micronized as the size of the mill is increased. Handling HPAPIs As with handling HPAPIs at any stage of process- ing, when looking to micronize potentially potent and harmful compounds, there are many consid- erations to weigh. Depending on the drug develop- Table I. The Biopharmaceutics Classification System (BCS). BCS Class Solubility Permeability Absorption Pattern I High High Well absorbed II Low High Well absorbed III High Low Variable IV Low Low Poorly absorbed

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